DESCRIPTION: This proposal is a competitive renewal of a study of the role of tissue kallikrein in blood pressure regulation. The investigators have evidence that tissue kallikrein plays a protective role in the pathogenesis of hypertension. They have developed a hypotensive transgenic mouse that overexpresses the human tissue kallikrein gene. They have also demonstrated that somatic gene delivery of human tissue kallikrein induces sustained reduction of blood pressure in spontaneously hypertensive rats (SHR). The current proposal will continue to investigate the role of tissue kallikrein in blood pressure regulation by (1) analyzing tissue kallikrein function by expressing human tissue kallikrein in specific tissues of transgenic mice and rats; (2) using homologous recombination techniques to knock out the kallikrein gene and to introduce a kallikrein antisense construct into transgenic mice; (3) analyzing the regulatory elements controlling the expression of the renal kallikrein gene in hypertensive and normotensive rats; (4) analyzing genetic linkage and association between human tissue kallikrein gene variants and hypertension in selected populations of humans; and lastly, (5) investigating the feasibility of delivering the human kallikrein gene into hypertensive rats by various gene transfer methods for somatic gene therapy.